Selective activation of PFKL suppresses the phagocytic oxidative burst

Amara, Neri; Cooper, Madison P.; Voronkova, Maria A.; Webb, Bradley A.; Lynch, E.M.; Kollman, Justin M.; Ma, Taylur; Yu, Kebing; Lai, Zijuan; Sangaraju, Dewakar; Kayagaki, Nobuhiko; Newton, Kim; Bogyo, Matthew; Staben, Steven T.; Dixit, Vishva M.

doi:10.1016/j.cell.2021.07.004

Cited by 92 publications

(70 citation statements)

References 75 publications

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“…While a prior report showed a requirement for GSDMD in PMA – induced NETosis 17 , we found that GSDMD had no apparent role in PMA or P. aeruginosa induced NETosis when quantified by Sytox or H3Cit and using either GSDMD-/- neutrophils or GSDMD chemical inhibitors. Further, the inhibitor used in that study (LDC7559) was found to block the oxidative burst rather than GSDMD 55 , although the difference between their findings using GSDMD mutant mice 17 and ours has yet to be determined.…”

Section: Discussioncontrasting

confidence: 52%

The NLRP3 inflammasome selectively drives IL-1β secretion byPseudomonas aeruginosainfected neutrophils and regulates bacterial killingin vivo

Minns

Lima

Liboro

et al. 2022

Preprint

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Macrophages infected with Gram-negative bacteria expressing flagellin or Type III secretion system (T3SS) structural proteins are known to activate the NLRC4 inflammasome, resulting in caspase-1 and Gasdermin D (GSDMD) cleavage, IL-1β secretion and pyroptotic cell death. We examined the role of these mediators in IL-1β secretion by neutrophils infected with Pseudomonas aeruginosa strain PAO1 that expresses the Type III secretion system (T3SS) effectors ExoS and ExoT. We found that IL-1β secretion by neutrophils was dependent on expression of the T3SS needle and translocon proteins. Although pro-GSDMD and pro-GSDME were processed in PAO1 infected neutrophils, only GSDMD was required for IL-1β secretion. PAO1 induced IL-1β secretion by macrophages was NLRC4 dependent, IL-1β secretion by neutrophils utilized NLRC4 only in the absence of P. aeruginosa exoenzymes. Instead, PAO1 induced IL-1β secretion required NLRP3, which mediated by ExoS ADP ribosyl transferase activity. We also found no role for GSDMD in NETosis induced by bacteria or PMA. Overall, these findings reveal fundamental differences between neutrophils and macrophages in IL-1β secretion in response to pathogenic bacteria.

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Section: Discussioncontrasting

confidence: 52%

The NLRP3 inflammasome selectively drives IL-1β secretion byPseudomonas aeruginosainfected neutrophils and regulates bacterial killingin vivo

Minns

Lima

Liboro

et al. 2022

Preprint

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“…5f,g ). Another report showed that treatment of cells with a PFK activator significantly lowered oxidative burst 40 . Activation of PFK can drain F6P.…”

Section: Resultsmentioning

confidence: 97%

“…Studies in acute oxidative stress suggest that PPP has high potential capacity to supply NADPH on demand 22 , 34 . Recent studies in various immune cells have additionally indicated the importance of PPP in immune functions 35 – 37 , including some in neutrophils suggesting the dependence of oxidative burst on glucose metabolism or oxPPP 38 – 40 . However, the specific metabolic reprogram that rapidly powers up neutrophil effector functions upon activation has not been quantitatively revealed.…”

Section: Mainmentioning

confidence: 99%

Switching to the cyclic pentose phosphate pathway powers the oxidative burst in activated neutrophils

et al. 2022

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Neutrophils are cells at the frontline of innate immunity that can quickly activate effector functions to eliminate pathogens upon stimulation. However, little is known about the metabolic adaptations that power these functions. Here we show rapid metabolic alterations in neutrophils upon activation, particularly drastic reconfiguration around the pentose phosphate pathway, which is specifically and quantitatively coupled to an oxidative burst. During this oxidative burst, neutrophils switch from glycolysis-dominant metabolism to a unique metabolic mode termed ‘pentose cycle’, where all glucose-6-phosphate is diverted into oxidative pentose phosphate pathway and net flux through upper glycolysis is reversed to allow substantial recycling of pentose phosphates. This reconfiguration maximizes NADPH yield to fuel superoxide production via NADPH oxidase. Disruptions of pentose cycle greatly suppress oxidative burst, the release of neutrophil extracellular traps and pathogen killing by neutrophils. Together, these results demonstrate the remarkable metabolic flexibility of neutrophils, which is essential for their functions as the first responders in innate immunity.

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“…It has been reported that the stabilization of HIF-1a up-regulate the pentose phosphate pathway ensuring the cytoplasmic supply of NADPH (42)(43)(44). Furthermore, the pharmacological activation of the glycolytic pathway through the phosphofructokinase-1 liver type, as it occurs during hypoxia, inhibits NET formation (45). In sum, low oxygen tensions prompt neutrophils to cause tissue damage through a sustained degranulation and secretion of reactive oxygen species and a reduction of pro-resolving NETs.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia Promotes Neutrophil Survival After Acute Myocardial Infarction

et al. 2022

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Phagocytosis, degranulation, and neutrophil extracellular traps (NETs) formation build the armory of neutrophils for the first line of defense against invading pathogens. All these processes are modulated by the microenvironment including tonicity, pH and oxygen levels. Here we investigated the neutrophil infiltration in cardiac tissue autopsy samples of patients with acute myocardial infarction (AMI) and compared these with tissues from patients with sepsis, endocarditis, dermal inflammation, abscesses and diseases with prominent neutrophil infiltration. We observed many neutrophils infiltrating the heart muscle after myocardial infarction. Most of these had viable morphology and only few showed signs of nuclear de-condensation, a hallmark of early NET formation. The abundance of NETs was the lowest in acute myocardial infarction when compared to other examined diseases. Since cardiac oxygen supply is abruptly abrogated in acute myocardial infarction, we hypothesized that the resulting tissue hypoxia increased the longevity of the neutrophils. Indeed, the viable cells showed increased nuclear hypoxia inducible factor-1α (HIF-1α) content, and only neutrophils with low HIF-1α started the process of NET formation (chromatin de-condensation and nuclear swelling). Prolonged neutrophil survival, increased oxidative burst and reduced NETs formation were reproduced under low oxygen tensions and by HIF-1α stabilization in vitro. We conclude that nuclear HIF-1α is associated with prolonged neutrophil survival and enhanced oxidative stress in hypoxic areas of AMI.

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Selective activation of PFKL suppresses the phagocytic oxidative burst

Cited by 92 publications

References 75 publications

The NLRP3 inflammasome selectively drives IL-1β secretion byPseudomonas aeruginosainfected neutrophils and regulates bacterial killingin vivo

The NLRP3 inflammasome selectively drives IL-1β secretion byPseudomonas aeruginosainfected neutrophils and regulates bacterial killingin vivo

Switching to the cyclic pentose phosphate pathway powers the oxidative burst in activated neutrophils

Hypoxia Promotes Neutrophil Survival After Acute Myocardial Infarction

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